Institute for Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany.
Clin Pharmacol Ther. 2018 May;103(5):868-878. doi: 10.1002/cpt.812. Epub 2017 Dec 8.
Fenoterol is a widely used anti-asthmatic and tocolytic agent, but high plasma concentrations of fenoterol may lead to severe and even fatal adverse reactions. We studied whether heritable deficiency of the liver organic cation transporter 1 (OCT1), a trait observed in 3% of Europeans and white Americans, affects fenoterol plasma concentrations and toxicity. OCT1 transported fenoterol with high affinity, and OCT1 inhibition in human hepatocytes reduced fenoterol uptake threefold. After administration of 180 µg of fenoterol to 39 healthy individuals, the OCT1-deficient individuals (zero active OCT1 alleles; n = 5) showed 1.9-fold greater systemic fenoterol exposure (P = 4.0 × 10 ) and 1.7-fold lower volume of distribution (P = 8.0 × 10 ). Correspondingly, the OCT1-deficient individuals had a 1.5-fold stronger increase in heart rate (P = 0.002), a 3.4-fold greater increase in blood glucose (P = 3.0 × 10 ), and significantly lower serum potassium levels. In conclusion, heritable OCT1 deficiency significantly increases plasma concentrations of fenoterol and may be an important factor underlying the excess mortality associated with fenoterol.
非诺特罗是一种广泛使用的抗哮喘和保胎药物，但高血浆浓度的非诺特罗可能导致严重甚至致命的不良反应。我们研究了肝脏有机阳离子转运蛋白 1（OCT1）遗传性缺乏（在 3%的欧洲人和白种美国人中观察到）是否会影响非诺特罗的血浆浓度和毒性。OCT1 对非诺特罗具有高亲和力，人肝细胞中 OCT1 的抑制作用使非诺特罗摄取减少了三倍。在 39 名健康个体中给予 180µg 非诺特罗后，OCT1 缺陷个体（零个活性 OCT1 等位基因；n=5）的全身非诺特罗暴露量增加了 1.9 倍（P=4.0×10），分布容积降低了 1.7 倍（P=8.0×10）。相应地，OCT1 缺陷个体的心率增加了 1.5 倍（P=0.002），血糖升高了 3.4 倍（P=3.0×10），血清钾水平显著降低。总之，遗传性 OCT1 缺乏显著增加了非诺特罗的血浆浓度，可能是与非诺特罗相关的死亡率增加的重要因素。
